Numerous biopolymers exhibit appealing characteristics for many industrial applications, for instance within the paper and textile industries but also within the pharmaceutical sciences and within various types of separation processes. Cellulose and hemicellulose are extensively characterized biopolymers of great significance not only as a basis for paper and textile manufacture but increasingly as drug delivery vehicles, for biomedical and biotechnological purposes, as well as solid phase component for various chromatographic separation techniques. The straight-chain hydrophilic cellulose possesses several interesting properties for pharmaceutical applications, for instance an absence of immunostimulatory properties and insusceptibility to enzymatic breakdown within the human body. Furthermore, its high mechanical rigidity has resulted in the use of cellulose as stationary phase for numerous separation applications.
Concomitant with the emergence of biotechnologically developed pharmaceuticals such as proteins, peptides, siRNAs, miRNAs, and antisense oligonucleotides, for the treatment of various diseases, the need for efficient delivery vehicles is greater than ever. Furthermore, improving delivery of conventional pharmaceuticals is in many cases critical in order to be able to increase dosage, decrease side effects, and improve pharmacokinetic properties. Encapsulating a drug of interest in a polymer shell is one way of improving its pharmacokinetic and possibly also its pharmaocodynamic properties, providing for instance sustained release over longer periods of time, formulations for local delivery, or protecting the drug from the harsh gastrointestinal environment or enzymatic breakdown upon per os administration.
Efficient separation processes are of vital importance within many industries, both for analytical and preparative purposes. The chemical industry, the pulp and paper industry, the petrochemical industry, as well as the medical and the pharmaceutical industries, among others, rely heavily on numerous separation process methodologies for various objectives. Separation is often based on chromatographic principles, i.e. passing the analyte-containing sample through a stationary, solid phase, in order to separate the components of the sample. The stationary phase is often composed of a polymeric material that exhibits certain properties forming the basis for the separation, for instance hydrophobicity, size, or ionic charge. The solid stationary phase furthermore needs to possess excellent characteristics in terms of, for instance, mechanical strength, chemical inertness and uniform size, in order to make the separation reliable and reproducible. Polymer shells are increasingly utilized as solid phase materials, as they possess many of the abovementioned characteristics, as well as the highly desired property of being able to function as a membrane with selective permeability for release and uptake of various molecules.
Polymer fibres for various purposes have long been produced using numerous techniques, but the preparation of shells, hollow substantially spherical particles, is still a complicated procedure. Cellulose fibres in the form of viscose have for instance been spun for almost a decade but a similar production of shells in a fast and reliable way naturally poses significantly more intricate problems. Spinning of fibres is normally based on applying a pressure on a dissolved polymer material and consequently forcing it out from a nozzle and into a bath where the fibres are formed, as a result of various chemical interactions. This approach is as of yet not possible for the production of polymer shells, as this would require the lumen of the fibres to be systematically divided. Currently, polymer shells based on cellulose are normally prepared in emulsions using methods relying on solvent diffusion and evaporation, an inefficient and to a certain extent time-consuming process, requiring the presence of additional coexcipients, such as polyethylene glycol, dibutyl phthalate, and polycaprolactone. Hollow beads composed of modified cellulose are also produced based on drop-wise addition to precipitation baths containing metal ions, resulting in subsequent precipitation of metal salts of polymer. This method, however, requires the beads to be cured in a curing bath containing additional metal ions. From a drug delivery perspective, the noticeable presence of metal ions may be a limiting aspect, possibly resulting in allergic reactions and undesired in vivo interactions. Furthermore, utilizing such shells for chromatographic purposes may limit the applicability only to certain types of separation, for instance based on ionic charge properties.
The polymer shells based on cellulose described in the prior art relate to non-responsive shells essentially displaying identical characteristics irrespective of the surrounding conditions. In order to prepare efficient drug delivery vehicles or stationary phase components of chromatographic systems, it is desirable to utilize shells with dynamic responsive properties. The ability to modulate, for instance, the permeability, the diameter, and the volume of polymer shells, would provide additional advantages e. g. increasing the release of a pharmaceutical composition upon exposure to certain external conditions, or modulating the properties of a chromatography column depending on the characteristics of the sample. Polymer shells displaying such characteristics are hitherto lacking in the prior art.
There is thus a need in the art for a rapid, simple, versatile, and robust manufacturing method without the use of excessive amounts of harsh chemicals for the preparation of polymer shells with responsive modifiable properties, for instance for drug delivery or chromatography purposes. Furthermore, carbohydrate polymer shells essentially only comprising the carbohydrate in question, resulting in minimized immunostimulatory properties and increased versatility within the field of chromatography, are lacking in prior art.
Prior art, SE 358 908, teaches the manufacture of hollow cellulose fibres, through spinning of viscose. The invention discloses a spinning bath containing a high concentration of magnesium ions, exerting a reducing effect on the swelling properties of the polymer when spinning viscose fibres through nozzles into said spinning bath.
U.S. Pat. No. 2,773,027 discloses a method for preparing hollow beads consisting of a metal salt of carboxymethyl cellulose, for use as a dialysis medium. An aqueous solution of carboxymethyl cellulose is drop-wise transferred into a precipitation bath consisting of a metal salt in an aqueous solution, wherein the metal salt-carboxymethyl cellulose beads are precipitated.
Soppimath and coworkers (Soppimath et al., 2006, Journal of Applied Polymer Science, 100, 486-494) describe a method based on the solvent-evaporation technique for the preparation of floating hollow microspheres using modified cellulose. Excipients such as polyethylene glycol, dibutyl phthalate, and polycaprolactone are utilized for the formation of the microspheres, with ethyl acetate acting as a dispersing solvent.
As an example of an efficient modification of the solvent evaporation technique, Utada and colleagues (Utada et al., 2005, Science, 308, 537-541) disclose a microcapillary device for generating monodisperse double emulsions containing a single internal droplet in a core-shell geometry, with a high degree of control and flexibility. The microcapillary system is further employed for the generation of polymeric vesicles using a water-in-oil-in-water emulsion comprising the diblock copolymer poly(butyl acrylate)-b-poly(acrylic acid) (PBA-PAA).